NP Inhibitory Ionotropic Receptors

Discuss the presence and need for inhibitory neurons in brain circuits

Inhibitory neurons play a crucial role in the modulation of neuronal circuits by preventing excessive excitatory signals

• Inhibitory neuron causes hyperpolarisation potential

  • This can remove the ability of a number of excitatory inputs to allow the neuron to reach threshold and fire an action potential

What are the two key fast inhibitory neurotransmitters?

• GABA (Gamma-Aminobutyric Acid): The major inhibitory neurotransmitter in the CNS.

• Glycine: Another key inhibitory neurotransmitter, particularly in the spinal cord.

Functional Properties: GABA A and Glycine receptors act as chloride channels, influencing neuronal excitability

Explain how GABAergic neuron signalling works (same as glycine neuron signalling)

• GABA is concentrated in the VIATT (vesicular amino acid transporter), when there is an influx of calcium due to an action potential, vesicle fuses with the presynaptic membrane and GABA gets released into synaptic cleft

• GABA interacts with the GABA receptors (ion channel) on the post synaptic membrane

Explain how GABA gets recycled/removed from the synaptic cleft

• GAT (GABA transporter) rapidly removes GABA from the synaptic cleft

  • Transport either into glial cells to be metabolised or recycled in the presynaptic cell for use as a neurotransmitter

What is the precurser for GABA?

The precursor for GABA is glutamate, the principle fast excitatory neurotransmitter

• Most post-synaptic neurons have both glutamate and GABA receptors

  • Thus, specificity between glutamate and GABA is ESSENTIAL

• Glutamic Acid Decarboxylase (GAD): Converts glutamate to GABA using pyridoxal phosphate (also uses a coenzyme called pyridoxal phosphate) in the presynaptic terminal

How does an AMPA receptor differentiate between glutamate and GABA?

Amino acids that form the binding pocket in the receptor are positioned perfectly for the oxygen to interact with glutamate in it's most relaxed form

• Even molecules with minor structural differences will not be able to bind and activate the receptor

Explain how GABA and glycine receptors work for inhibition in terms of ion movement.

Through chloride or potassium ions.

- For chloride ions, their equilibrium potential is around -64mV, close to the resting membrane potential of -65mV. This proximity indicates that chloride ions can effectively stabilize the membrane potential when channels are opened, preventing excessive depolarization and maintaining neuronal inhibition. In a mature neuron, there is a potassium chloride co-transporter that ensures that the concentration of chloride within the cell is relatively low. This means that when the chloride channel is opened, chloride will move into the neuron, making the interior of the cell more negative (hyperpolarisation).

• Inhibition can also occur through increased potassium conductance, which further reinforces the importance of equilibrium potential in the functioning of inhibitory neurons in modulating excitatory signals.

Is GABA always inhibitory?

• No, GABA is not always inhibitory

  • During the maturation of the nervous system, GABA changes from excitatory to inhibitory

• Now the high intracellular cellular concentration of chloride ions means the equilibrium potential of the chloride will be higher (less negative) than the resting membrane potential, meaning that if you open the chloride channel, chloride will leave the neurone, and the neuron will depolarise, meaning the chloride becomes excitatory.